Archief Roodbont

Time to retire warfarin from stroke prevention in atrial fibrillation?

Freek Verheugt
Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands

21 December 2010

Oral anticoagulation with warfarin remains the cornerstone of stroke prevention in patients with atrial fibrillation (AF). But warfarin can be difficult to manage, and around half of AF patients at risk for stroke are either unable or unwilling to take it.

Evidence is now emerging that some novel antithrombotic agents may offer effective alternatives to warfarin. Two recent trials of oral factor Xa inhibitors in AF patients, the AVERROES trial evaluating apixaban and ROCKET-AF trial studying rivaroxaban, have produced promising results.

MedWire spoke to Professor Freek Verheugt at the recent American Heart Association (AHA) Scientific Sessions 2010 in Chicago, Illinois, to hear his thoughts on AVERROES (Apixaban versus Acetysalicylic Acid to Prevent Strokes) and ROCKET-AF (Rivaroxaban in Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), what they mean for patients, and how to interpret them in the light of other recently reported and ongoing trials of novel antithrombotics in AF.

Addressing a major unmet need
Patients with atrial fibrillation (AF) are at very high risk for stroke, with a five times greater risk than people without the arrhythmia. Vitamin K antagonists, such as warfarin, reduce the risk for stroke by two-thirds compared with placebo [1], and by one-third when compared with aspirin or the combination of aspirin and clopidogrel [2,3].

However, Verheugt explains, only half of patients with AF are diagnosed with the arrhythmia in the first place. Of these, only half receive treatment with an anticoagulant, and in turn, only half are adequately anticoagulated.

“So only one out of eight patients with AF is properly anticoagulated, which I think shows there is a huge unmet need,” he stresses.

Part of the problem is that warfarin increases the risk for severe bleeding complications, the most dangerous being cerebral bleeding (intracranial hemorrhage [ICH]) [4]. Furthermore, response to warfarin is unpredictable, and patients need careful monitoring to make sure they remain within the therapeutic international normalized ratio (INR) range.

Doctors are therefore often reluctant to prescribe warfarin, particularly if the patient is unlikely to comply with monitoring because of dementia or alcohol misuse, or is at risk of falls or head trauma. And patients themselves may fear the bleeding complications and prefer not to have to go through monitoring. As a consequence, an estimated 40–50% of AF patients who are at moderate or high risk for stroke and would benefit from warfarin treatment do not receive it [5,6].

The standard of care for AF patients at risk for stroke but considered unsuitable for a vitamin K antagonist has been aspirin [7], or more recently, the combination of aspirin and clopidogrel [8]. But these drugs offer relatively weak antithrombotic protection against stroke, and are also associated with increased bleeding risks. The AVERROES trial sought to address the unmet need in this group of patients, aiming to demonstrate that apixaban is superior to aspirin for stroke prevention. Most trials evaluating alternative anticoagulants for stroke prevention in AF focus on demonstrating noninferiority to warfarin, however, and this was the approach adopted in the ROCKET-AF trial.

AVERROES – an alternative solution
The AVERROES trial included 5600 AF patients, aged an average of 70 years, at moderate or high risk for stroke (mean CHADS2 score 2.1) who were randomly assigned to receive apixaban 5 mg twice daily or aspirin 81–324 mg once daily for up to 3 years.

The trial was halted early after interim analysis showed a significant 54% reduction in the relative risk for stroke or systemic embolism, the primary endpoint. Importantly, this benefit was seen without an increase in bleeding risk. The relative risk for the primary safety endpoint of major bleeding was 14% higher in the apixaban compared with the aspirin group, a statistically nonsignificant difference. And, although there was a moderate increase in minor bleeding, there was no difference in the most feared bleeding complication, ICH.

“The outcome was smashingly positive – a 50% reduction of stroke and systemic embolism. A little bit as expected, because aspirin as we know is not a very effective drug for stroke prevention,” says Verheugt.

“What was unexpected was the low rate of bleeding with apixaban – particularly because doctors felt in about half of cases the patients were unsuitable for a vitamin K antagonist because of falling. Yet cerebral bleeding [ICH] was similar in each group – which is amazing.”

Table 1: AVERROES outcomes – annual event rates

	Apixaban (n=2809)	Aspirin (n=2791)	Relative risk (95% confidence interval)	p-value
Primary endpoint Stroke or systemic embolism	1.6	3.6	0.46(0.33–0.64)	<0.001
Primary safety endpoint Major bleeding	1.4	1.2	1.14 (0.74–1.75)	0.56
Other safety endpoints Minor bleeding ICH Fatal bleeding	5.2 0.4 0.1	4.1 0.3 0.1	1.27 (1.01–1.61) 1.09 (0.50–2.39) 0.84 (0.26–2.75)	0.04 0.83 0.77

Abbreviations: ICH, intracranial hemorrhage.

VERROES have yet to be published, but should yield important information on the risk-benefit ratio of apixaban according to stroke risk, age, and reason for warfarin contraindication. They should also address the wide dosing range in the aspirin arm.

Verheugt explains: “That was one of the criticisms of the trial – that the only really effective dose for stroke prevention in AF is 325 mg. But it’s so uncommonly prescribed in Europe, because of the associated gastrointestinal bleeding at higher doses.”

Some critics also queried the rationale behind AVERROES. Verheugt himself questions how many patients are truly unsuitable for warfarin therapy [9], and other commentators asked whether it was ethical to test an attractive anticoagulant against aspirin, which is considered rather ineffective. But he points out that in practice, these patients would not have been given anything more than aspirin.

How apixaban compares with warfarin should become clearer with the results of the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation) trial, due to be reported at the European Society of Cardiology Annual Conference in 2011 [10]. In the meantime, top-line results of the ROCKET-AF trial comparing rivaroxaban with warfarin that were released last month underlined the potential of this class of drugs.

ROCKET-AF – rivaroxaban has lift off
The ROCKET-AF trial included over 14,000 AF patients aged an average of 73 years at moderate or high risk for stroke (mean CHADS2 score 3.5). Patients were randomly assigned to rivaroxaban 20 mg once daily or warfarin (target INR of 2.0–3.0) in a double-blind, double-dummy design, and followed-up for 1.9 years.

Patients who received rivaroxaban had a significant 21% reduction in risk for stroke or non-central nervous system (CNS) embolism relative to those taking warfarin, by per-protocol analysis, meaning that rivaroxaban met criteria for non-inferiority to warfarin.

Table 2: ROCKET-AF outcomes – event rates per 100 patient-years

	Rivaroxaban (n=7081)	Warfarin (n=7090)	Hazard ratio (95% confidence interval)	p-value
Primary efficacy endpoint Stroke, non-CNS embolism	1.71	2.16	0.79 (0.66–0.96)	<0.001>
Primary safety endpoint Major or non-major clinically relevant bleeding	14.91	14.52	1.03 (0.96–1.11)	0.442
Other safety endpoints ICH Fatal bleeding	0.49 0.24	0.74 0.48	0.67 (0.47–0.94) 0.50 (0.31–0.79)	0.019 0.003

Importantly, there was no increased risk for bleeding events with rivaroxaban compared with warfarin. In fact, there was a significant reduction in the risk for ICH with rivaroxaban, which Verheugt says is “very reassuring,” as well as for fatal bleeding.

Although the results demonstrated noninferiority to warfarin, the primary efficacy endpoint did not differ significantly between groups by “gold standard” intention-to-treat analysis. So how does this leave rivaroxaban relative to the direct thrombin inhibitor dabigatran, which was found to be superior to warfarin in the RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial? [11].

Verheugt says: “The RE-LY study showed superiority, but it was in an open-label trial – simpler to do but more difficult to interpret because when doctors and patients know their treatment allocation you get a lot of bias in reporting events, even efficacy endpoints as well as safety events. So I have my doubts whether dabigatran is really superior to warfarin.”

In addition, the study population in ROCKET-AF represented a much more high-risk, complex group of patients than that in RE-LY. On the other hand, the time in therapeutic range in the warfarin group in ROCKET-AF was considered low, at 57.8%, suggesting that the performance of warfarin was not quite what it could be.

Despite this, Verheugt emphasizes: “To even come close to warfarin, which is extremely effective, is very good. And to show equivalence really is a major finding.”

From rags to riches
Guidelines and regulatory bodies will take some time to catch up with these latest developments. But Verheugt says that after decades of returning to the “old workhorse” warfarin, doctors could soon have as many as four alternative new antithrombotics to choose from.

Apixaban is unique in having data to support its use in the large group of AF patients deemed unsuitable for warfarin. Dabigatran is already approved for AF in the USA, and has entered Canadian guidelines, but Verheugt emphasizes that it has not been tested in this group of patients specifically and that the dosing remains uncertain.

Verheugt also believes that the increased rate of myocardial infarctions (MIs) with dabigatran seen in RE-LY could be an Achilles heel, noting that “the consequences of MI are much worse in the elderly.” This risk was seen with another univalent direct thrombin inhibitor, ximelagatran, development of which was abandoned because of associated liver toxicity.

There was no evidence of excess MIs with rivaroxaban in ROCKET-AF, Verheugt notes, although the study duration was short and the overall MI rate low. “So we have to wait for ARISTOTLE – if that study also finds no increase in MIs I think that it’s quite possible there is a class effect of the direct thrombin blockers, which you would like to avoid in the elderly.”

In addition, another promising oral factor Xa inhibitor, edoxaban, is being tested against warfarin in a similar population to that of RE-LY in the ENGAGE AF-TIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation) trial, which is due to report in 2012 [12].

The ‘old workhorse’ to retire?
Despite the potential of these newer drugs, Verheugt remains a strong proponent of warfarin. He believes that with proper monitoring systems and improved awareness and patient information, many patients deemed unsuitable for warfarin therapy could, in fact, take it [9].

“I have my severe doubts that this is a distinct group of patients. Yes, sometimes, people really are not suitable, but most of the patients could be given warfarin,” he says.

The monitoring process also provides a useful way of ensuring compliance as well as checking up on patients’ general health, he explains. In addition, many healthcare systems will have to establish whether the increased cost of the newer drugs can be justified. Some European and Scandinavian countries have such well established networks of warfarin monitoring clinics that the cost of warfarin is negligible, Verheugt points out. In these countries there may be considerable resistance to paying for the newer alternatives. Despite these caveats, however, Verheugt concedes that warfarin may finally be on its way out.

“I have to admit we now have two big trials that show an effective alternative, probably with a better safety profile, compared with warfarin,” he says. “Doctors love to hate warfarin, especially in the USA. And for simplicity, of course, doctors like these new drugs, to be able to just give a prescription.

“So in the end I think warfarin, the ‘old workhorse’, will take honorable retirement.”